This invention relates to novel lactams having drug and bio-affecting properties, their pharmaceutical compositions and methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Axcex2-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to xcex2-amyloid production such as Alzheimer""s disease and Down""s Syndrome.
Alzheimer""s disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, temporal and local orientation, cognition, reasoning, judgment and emotionally stability. AD is a common cause of progressive dementia in humans and is one of the major causes of death in the United States. AD has been observed in all races and ethnic groups worldwide, and is a major present and future health problem. No treatment that effectively prevents AD or reverses the clinical symptoms and underlying pathophysiology is currently available (for review see, Dennis J. Selkoe; Cell Biology of the amyloid (beta)-protein precursor and the mechanism of Alzheimer""s disease, Annu Rev Cell Biol, 1994, 10: 373-403).
Histopathological examination of brain tissue derived upon autopsy or from neurosurgical specimens in effected individuals revealed the occurrence of amyloid plaques and neurofibrillar tangles in the cerebral cortex of such patients. Similar alterations were observed in patients with Trisomy 21 (Down""s syndrome), and hereditary cerebral hemorrhage with amyloidosis of the Dutch-type. Neurofibrillar tangles are nonmembrane-bound bundles of abnormal proteinaceous filaments and biochemical and immunochemical studies led to the conclusion that their principle protein subunit is an altered phosphorylated form of the tau protein (reviewed in Selkoe, 1994).
Biochemical and immunological studies revealed that the dominant proteinaceous component of the amyloid plaque is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids. This protein was designated Axcex2, xcex2-amyloid peptide, and sometimes xcex2/A4; referred to herein as Axcex2. In addition to its deposition in amyloid plaques, Axcex2 is also found in the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. Axcex2 was first purified and a partial amino acid reported in 1984 (Glenner and Wong, Biochem. Biophys. Res. Commun. 120: 885-890). The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No 4,666,829.
Compelling evidence accumulated during the last decade revealed that Axcex2 is an internal polypeptide derived from a type 1 integral membrane protein, termed xcex2 amyloid precursor protein (APP). xcex2 APP is normally produced by many cells both in vivo and in cultured cells, derived from various animals and humans. xcex2 is derived from cleavage of xcex2 APP by as yet unknown enzyme (protease) system(s), collectively termed secretases.
The existence of at least four proteolytic activities has been postulated. They include xcex2 secretase(s), generating the N-terminus of Axcex2, xcex1 secretase(s) cleaving around the 16/17 peptide bond in Axcex2, and xcex3 secretases, generating C-terminal Axcex2 fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.
Several lines of evidence suggest that abnormal accumulation of Axcex2 plays a key role in the pathogenesis of AD. Firstly, Axcex2 is the major protein found in amyloid plaques. Secondly, Axcex2 is neurotoxic and may be causally related to neuronal death observed in AD patients. Thirdly, missense DNA mutations at position 717 in the 770 isoform of xcex2 APP can be found in effected members but not unaffected members of several families with a genetically determined (familiar) form of AD. In addition, several other xcex2 APP mutations have been described in familiar forms of AD. Fourthly, similar neuropathological changes have been observed in transgenic animals overexpressing mutant forms of human xcex2 APP. Fifthly, individuals with Down""s syndrome have an increased gene dosage of xcex2 APP and develop early-onset AD. Taken together, these observations strongly suggest that Axcex2 depositions may be causally related to the AD.
It is hypothesized that inhibiting the production of Axcex2 will prevent and reduce neurological degeneration, by controlling the formation of amyloid plaques, reducing neurotoxicity and, generally, mediating the pathology associated with Axcex2 production. One method of treatment methods would therefore be based on drugs that inhibit the formation of Axcex2 in vivo.
Methods of treatment could target the formation of Axcex2 through the enzymes involved in the proteolytic processing of xcex2 amyloid precursor protein. Compounds that inhibit xcex2 or xcex3secretase activity, either directly or indirectly, could control the production of Axcex2. Advantageously, compounds that specifically target xcex3 secretases, could control the production of Axcex2. Such inhibition of xcex2 or xcex3secretases could thereby reduce production of Axcex2, which, thereby, could reduce or prevent the neurological disorders associated with Axcex2 protein.
PCT publication number WO 96/29313 discloses the general formula: 
covering metalloprotease inhibiting compounds useful for the treatment of diseases associated with excess and/or unwanted matrix metalloprotease activity, particularly collagenase and or stromelysin activity.
Compounds of general formula: 
are disclosed in PCT publication number WO 95/22966 relating to matrix metalloprotease inhibitors. The compounds of the invention are useful for the treatment of conditions associated with the destruction of cartilage, including corneal ulceration, osteoporosis, periodontitis and cancer.
European Patent Application number EP 0652009A1 relates to the general formula: 
and discloses compounds that are protease inhibitors that inhibit Axcex2 production.
U.S. Pat. No. 5,703,129 discloses the general formula: 
which covers 5-amino-6-cyclohexyl-4-hydroxy-hexanamide derivatives that inhibit Axcex2 production and are useful in the treatment of Alzheimer""s disease.
Copending, commonly assigned U.S. patent application Ser. No. 09/370,089 filed Aug. 7, 1999 (equivalent to international application PCT US99/17717) discloses lactams of general formula: 
wherein the lactam ring B is substituted by succinamide and a carbocyclic, aryl, or heteroaryl group. These compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Axcex2-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein.
None of the above references teaches or suggests the compounds of the present invention which are described in detail below.
One object of the present invention is to provide novel compounds which are useful as inhibitors of the production of Axcex2 protein or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating degenerative neurological disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors discovery that compounds of Formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein R3, R3a, R5, R5a, R6, Q, B, W, X, Y, and Z are defined below, are effective inhibitors of the production of Axcex2 protein.
Thus, in a first embodiment, the present invention provides a novel compound of Formula (I): 
or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
Q is
xe2x80x94(CR7R7a)mxe2x80x94R4,
xe2x80x94(CR7R7a)mxe2x80x94CH(OH)xe2x80x94R4,
xe2x80x94(CR7R7a)mmxe2x80x94NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94Sxe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94Oxe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94N(R7b)xe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94S(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94S(xe2x95x90O)2xe2x80x94R4, or
xe2x80x94(CR7R7a)nxe2x80x94C(xe2x95x90O)xe2x80x94R4;
m is 1, 2, or 3;
n is 0, 1, or 2;
R4 is H,
C1-C8 alkyl substituted with 0-3 R4a,
C2-C8 alkenyl substituted with 0-3 R4a,
C2-C8 alkynyl substituted with 0-3 R4a,
C3-C10 carbocycle substituted with 0-3 R4b,
C6-C10 aryl substituted with 0-3 R4b, or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R4b;
R4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, CF3, C1-C3 alkyl,
C3-C10 carbocycle substituted with 0-3 R4b,
C6-C10 aryl substituted with 0-3 R4b, and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R5 and R5a are combined to form a 3-8 membered carbocyclic moiety;
wherein said 3-8 membered carbocyclic moiety is saturated or partially unsaturated;
wherein said 3-8 membered carbocyclic moiety may optionally contain a heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, and xe2x80x94N(R20)xe2x80x94; and
wherein said 3-8 membered carbocyclic moiety is substituted with 0-4 R5b;
additionally, two R5b substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R23;
additionally, two R5b substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R23;
additionally, two R5b substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R23;
R5b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, NR15R16, OR14a, C1-C4 alkyl, C2-C6 alkenyl, alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl-Sxe2x80x94, C3-C6 carbocycle, phenyl, and a 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur;
R6 is H;
C1-C6 alkyl substituted with 0-3 R6a;
C3-C10 carbocycle substituted with 0-3 R6b; or
C6-C10 aryl substituted with 0-3 R6b;
R6a, at each occurrence, is independently selected from H,
C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, aryl and CF3;
R6b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R7a, at each occurrence, is independently H or C1-C4 alkyl;
R7a, at each occurrence, is independently H or C1-C4 alkyl;
R7b is H, C1-C4 alkyl, or (C1-C4 alkyl)OC(xe2x95x90O)xe2x80x94;
Ring B is a 7 membered lactam,
wherein the lactam is saturated, partially saturated or unsaturated;
wherein each additional lactam carbon is substituted with 0-2 R11; and,
optionally, the lactam contains a heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, and xe2x80x94N(R10)xe2x80x94;
additionally, two R11 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R13;
additionally, two R11 substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R13;
additionally, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R13;
R10 is H, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, S(xe2x95x90O)2R17;
C1-C6 alkyl optionally substituted with 0-3 R10a;
C6-C10 aryl substituted with 0-4 R10b;
C3-C10 carbocycle substituted with 0-3 R10b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R10b;
R10a, at each occurrence, is independently selected from:
H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, N2, NR15R16, CF3;
aryl substituted with 0-4 R10b;
C3-C10 carbocycle substituted with 0-3 R10b; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R10b;
R10b, at each occurrence, is independently selected from H,
OH, Cl, F, Br, I, CN, N2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R11, at each occurrence, is independently selected from H, C1-C4 alkoxy, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR18R19, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, CF3;
C1-C6 alkyl optionally substituted with 0-3 R11a;
C6-C10 aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3;
phenyl substituted with 0-3 R11b;
C3-C6 cycloalkyl substituted with 0-3 R11b; and
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H,
OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
W is a bond or xe2x80x94(CR8R8a)pxe2x80x94;
p is 0, 1, 2, 3, or 4;
R8 and R8a, at each occurrence, are independently selected from H, F, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C8 cycloalkyl;
X is a bond;
C6-C10 aryl substituted with 0-3 RXb;
C3-C10 carbocycle substituted with 0-3 RXb; or
5 to 10 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
Y is a bond or xe2x80x94(CR9R9a)txe2x80x94Vxe2x80x94(CR9R9a)uxe2x80x94;
t is 0, 1, or 2;
u is 0, 1, or 2;
R9 and R9a, at each occurrence, are independently selected from H, F, C1-C6 alkyl or C3-C8 cycloalkyl;
V is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94N(R19)xe2x80x94, xe2x80x94C(xe2x95x90O)NR19bxe2x80x94, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)NR19xe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, or
xe2x80x94OC (xe2x95x90O)xe2x80x94;
Z is H;
C1-C8 alkyl substituted with 0-3 R12a;
C2-C6 alkenyl substituted with 0-3 R12a;
C2-C6 alkynyl substituted with 0-3 R12a;
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, xe2x80x94C(xe2x95x90O)NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl-Sxe2x80x94,
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, aryl, C3-C6 cycloalkyl, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R13, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, N2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C6 alkyl, C2-C6 alkoxyalkyl, or
C3-C6 cycloalkyl;
R14a is H, phenyl, benzyl, or C1-C4 alkyl;
R15, at each occurrence, is independently selected from H,
C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)xe2x80x94C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)xe2x80x94S(xe2x95x90O)2xe2x80x94;
R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)xe2x80x94C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)xe2x80x94S(xe2x95x90O)2xe2x80x94;
R17 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl, aryl substituted by 0-4 R17a, or xe2x80x94CH2-aryl substituted by 0-4 R17a;
R17a is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, xe2x80x94OH, F, Cl, Br, I, CF3, OCF3, SCH3,
S(O)CH3, SO2CH3, xe2x80x94NH2, xe2x80x94N(CH3)2, or C1-C4 haloalkyl;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, aryl, aryl-CH2xe2x80x94, aryl-CH2CH2xe2x80x94, (C1-C6 alkyl)xe2x80x94C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)xe2x80x94S(xe2x95x90O)2xe2x80x94;
R19, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, aryl, aryl-CH2xe2x80x94, aryl-CH2CH2xe2x80x94, (C1-C6 alkyl)xe2x80x94C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)xe2x80x94S(xe2x95x90O)2xe2x80x94;
R19b, at each occurrence, is independently is H or C1-C4 alkyl;
R20 is H, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, S(xe2x95x90O)2R17;
C1-C6 alkyl optionally substituted with 0-3 R20a; or
C6-C10 aryl substituted with 0-4 R20b;
R20a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, and aryl substituted with 0-4 R20b;
R20b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94; and
R23, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
provided when Q is xe2x80x94(CR7R7a)nxe2x80x94N(R7b)xe2x80x94R4 and R7b is (C1-C4alkyl)OC(xe2x95x90O)xe2x80x94, then n is 1 or 2; and
provided when Q is xe2x80x94(CR7R7a)nxe2x80x94N(R7b)xe2x80x94R4 and n is 0, then R4 
does not contain a xe2x80x94C(xe2x95x90O)xe2x80x94 adjacent to xe2x80x94N(R7b)xe2x80x94.
[2] In a preferred embodiment the present invention provides for a compound of Formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
Q is
xe2x80x94(CR7R7a)mxe2x80x94R4,
xe2x80x94(CR7R7a)mxe2x80x94CH(OH)xe2x80x94R4,
xe2x80x94(CR7R7a)mxe2x80x94NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94Sxe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94Oxe2x80x94R4, or
xe2x80x94(CR7R7a)nxe2x80x94N(R7b)xe2x80x94R4;
m is 1 or 2;
n is 0 or 1;
R4 is H,
C1-C8 alkyl substituted with 0-3 R4a,
C2-C8 alkenyl substituted with 0-3 R4a,
C2-C8 alkynyl substituted with 0-3 R4a,
C3-C10 carbocycle substituted with 0-3 R4b,
C6-C10 aryl substituted with 0-3 R4b, or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R4b;
R4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, CF3, C1-C3 alkyl,
C3-C10 carbocycle substituted with 0-3 R4b,
C6-C10 aryl substituted with 0-3 R4b, and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R5 and R5a are combined to form a 3-8 membered carbocyclic moiety;
wherein said 3-8 membered carbocyclic moiety is saturated or partially unsaturated;
wherein said 3-8 membered carbocyclic moiety may optionally contain a heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94N(R20)xe2x80x94; and
wherein said 3-8 membered carbocyclic moiety is substituted with 0-4 R5b;
additionally, two R5b substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R23;
additionally, two R5b substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R23;
additionally, two R5b substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R23;
R5b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, N2, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, NR15R16, OR14a, C1-C4 alkyl, C2-C6 alkenyl, alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl-Sxe2x80x94,
C3-C6 carbocycle, phenyl, and a
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur;
R6 is H, methyl, or ethyl;
R7 at each occurrence, is independently H or C1-C4 alkyl;
R7a, at each occurrence, is independently H or C1-C4 alkyl;
R7b is H, C1-C4 alkyl, or (C1-C4 alkyl)OC(xe2x95x90O)xe2x80x94;
Ring B is selected from: 
R10 is H, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, S(xe2x95x90O)2R17;
C1-C6 alkyl optionally substituted with 0-3 R10a ;
C6-C10 aryl substituted with 0-4 R10b;
C3-C10 carbocycle substituted with 0-3 R10b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R10b;
R10a, at each occurrence, is independently selected from: H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3;
aryl substituted with 0-4 R10b;
C3-C10 carbocycle substituted with 0-3 R10b; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R10b;
R10b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R11, at each occurrence, is independently selected from
H, C1-C4 alkoxy, Cl, F, Br, I, xe2x95x90O, CN, N2, NR18R19, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, CF3;
C1-C6 alkyl optionally substituted with 0-3 R11a;
C6-C10 aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3;
phenyl substituted with 0-3 R11b;
C3-C6 cycloalkyl substituted with 0-3 R11b ; and
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
W is a bond or xe2x80x94(CH2)pxe2x80x94;
p is 1 or 2;
X is a bond;
phenyl substituted with 0-2 RXb;
C3-C6 carbocycle substituted with 0-2 RXb; or
5 to 6 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, and C1-C3 halothioalkoxy;
Y is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94N(R19)xe2x80x94, xe2x80x94C(xe2x95x90O)NR19bxe2x80x94, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)NR19bxe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, or xe2x80x94OC(xe2x95x90O)xe2x80x94;
Z is H;
C1-C8 alkyl substituted with 0-3 R12a;
C2-C6 alkenyl substituted with 0-3 R12a;
C2-C6 alkynyl substituted with 0-3 R12a;
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, xe2x80x94C(xe2x95x90O)NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl-Sxe2x80x94,
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
R14ais H, phenyl, benzyl, or C1-C4 alkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)xe2x80x94S(xe2x95x90O)2xe2x80x94;
R16, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, benzyl, phenethyl,
(C1-C6 alkyl)xe2x80x94C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)xe2x80x94S(xe2x95x90O)2xe2x80x94;
R17 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl, aryl substituted by 0-4 R17a, or xe2x80x94CH2-aryl substituted by 0-4 R17a;
R17a is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, xe2x80x94OH, F, Cl, Br, I, CF3, OCF3, SCH3, S(O)CH3, SO2CH3, xe2x80x94NH2, xe2x80x94N(CH3)2, or C1-C4 haloalkyl;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)xe2x80x94C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)xe2x80x94S(xe2x95x90O)2xe2x80x94;
R19, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R19b, at each occurrence, is independently is H or C1-C4 alkyl;
R20 is C(xe2x95x90O)OR17;
R23, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
provided when Q is xe2x80x94(CR7R7a)nxe2x80x94N(R7b)xe2x80x94R4 and R7bis (C1-C4 alkyl)OC(xe2x95x90O)xe2x80x94, then n is 1 or 2; and
provided when Q is xe2x80x94(CR7R7a)nxe2x80x94N(R7b)xe2x80x94R4 and n is 0, then R4 does not contain a xe2x80x94C(xe2x95x90O)xe2x80x94 adjacent to xe2x80x94N(R7b)xe2x80x94.
[3] In a more preferred embodiment the present invention provides for a compound of Formula (Ia): 
or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
Q is
xe2x80x94(CHR7a)mxe2x80x94R4,
xe2x80x94(CHR7a)mxe2x80x94CH(OH)xe2x80x94R4,
xe2x80x94(CHR7a)mxe2x80x94NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CHR7a)nxe2x80x94Sxe2x80x94R4,
xe2x80x94(CHR7a)nxe2x80x94xe2x80x94Oxe2x80x94R4, or
xe2x80x94(CHR7a)nxe2x80x94N (R7b)xe2x80x94R4;
m is 1 or 2;
n is 0 or 1;
R4 is H,
C1-C8 alkyl substituted with 0-3 R4a,
C2-C8 alkenyl substituted with 0-3 R4a,
C2-C8 alkynyl substituted with 0-3 R4a,
C3-C10 carbocycle substituted with 0-3 R4b,
C6-C10 aryl substituted with 0-3 R4b, or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R4b;
R4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, CF3, methyl, ethyl,
C3-C10 carbocycle substituted with 0-3 R4b,
C6-C10 aryl substituted with 0-3 R4b, and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, N2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R5 and R5a are combined to form a 3-8 membered carbocyclic moiety;
wherein said 3-8 membered carbocyclic moiety is saturated or partially unsaturated;
wherein said 3-8 membered carbocyclic moiety may optionally contain a heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94N(R20)xe2x80x94; and
wherein said 3-8 membered carbocyclic moiety is substituted with 0-4 R5b;
additionally, two R5bsubstituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R23;
additionally, two R5bsubstituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R23;
additionally, two R5b substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R23;
R5b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, NR15R16, OR14a, C1-C4 alkyl, C2-C6 alkenyl, alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94,
C3-C6 carbocycle, phenyl, and a
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur;
R7a, at each occurrence, is independently H, methyl, or ethyl;
R7b is H, methyl, ethyl, CH3OC(xe2x95x90O)xe2x80x94, or CH3CH2OC(xe2x95x90O)xe2x80x94;
Ring B is selected from: 
R11, at each occurrence, is independently selected from H, C1-C4 alkoxy, Cl, F, Br, I, xe2x95x90O, CN, N2, NR18R19, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, CF3;
C1-C6 alkyl optionally substituted with 0-3 R11a;
C6-C10 aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3;
phenyl substituted with 0-3 R11b;
C3-C6 cycloalkyl substituted with 0-3 R11b; and
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R11b;
R11b at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3,
S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
W is a bond;
X is a bond;
Y is a bond;
Z is H;
C1-C8 alkyl substituted with 0-3 R12a;
C2-C6 alkenyl substituted with 0-3 R12a;
C2-C6 alkynyl substituted with 0-3 R12a;
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, xe2x80x94C(xe2x95x90O)NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl-Sxe2x80x94,
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
R14a is H, phenyl, benzyl, or C1-C4 alkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)xe2x80x94C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)xe2x80x94S(xe2x95x90O)2xe2x80x94;
R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)xe2x80x94C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)xe2x80x94S(xe2x95x90O)2xe2x80x94;
R17 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl,
aryl substituted by 0-4 R17a, or
xe2x80x94CH2-aryl substituted by 0-4 R17a;
R7a is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, xe2x80x94OH, F, Cl, Br, I, CF3, OCF3, SCH3, S(O)CH3, SO2CH3, xe2x80x94NH2, xe2x80x94N(CH3)2, or C1-C4 haloalkyl;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)xe2x80x94C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)xe2x80x94S(xe2x95x90O)2xe2x80x94;
R19, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R23, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
provided when Q is xe2x80x94(CHR7a)nxe2x80x94N(R7b)xe2x80x94R4 and R7b is (C1-C4 alkyl)OC(xe2x95x90O)xe2x80x94, then n is 1 or 2; and
provided when Q is xe2x80x94(CHR7a)nxe2x80x94N(R7b)xe2x80x94R4 and n is O, then R4 does not contain a xe2x80x94C(xe2x95x90O)xe2x80x94 adjacent to xe2x80x94N(R7b)xe2x80x94.
[4] In a further more preferred embodiment the present invention provides for a compound of Formula (Ia) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
Q is
xe2x80x94(CH2)mxe2x80x94R4,
xe2x80x94(CH2)mxe2x80x94CH(OH)xe2x80x94R4,
xe2x80x94(CH2)mxe2x80x94NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)nxe2x80x94Sxe2x80x94R4,
xe2x80x94(CH2)nxe2x80x94Oxe2x80x94R4, or
xe2x80x94(CH2)nxe2x80x94xe2x80x94N(R7b)xe2x80x94R4;
m is 1 or 2;
n is 0 or 1;
R4 is
C1-C8 alkyl substituted with 0-3 R4a,
C2-C8 alkenyl substituted with 0-3 R4a,
C2-C8 alkynyl substituted with 0-3 R4a,
C3-C10 carbocycle substituted with 0-3 R4b,
C6-C10 aryl substituted with 0-3 R4b, or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R4b;
R4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, CF3, methyl,
C3-C10 carbocycle substituted with 0-3 R4b,
C6-C10 aryl substituted with 0-3 R4b, and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R5 and R5aare combined to form a 3-8 membered carbocyclic moiety;
wherein said 3-8 membered carbocyclic moiety is saturated or partially unsaturated;
wherein said 3-8 membered carbocyclic moiety may optionally contain a heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94N(R20)xe2x80x94; and
wherein said 3-8 membered carbocyclic moiety is substituted with 0-3 R5b;
R5b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, NR15R16, OR14a, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R7b is H, methyl, ethyl, CH3OC(xe2x95x90O)xe2x80x94, or CH3CH2OC(xe2x95x90O)xe2x80x94;
Ring B is selected from: 
R11, at each occurrence, is independently selected from H, xe2x95x90O, NR18R19, CF3;
C1-C4 alkyl optionally substituted with 0-1 R11a; phenyl substituted with 0-3 R11b;
C3-C6 carbocycle substituted with 0-3 R11b; and
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R11a, at each occurrence, is independently selected from H, C10-C4 alkyl, OR14, F, Cl, xe2x95x90O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
W is a bond;
X is a bond;
Y is a bond;
Z is H;
C1-C8 alkyl substituted with 0-3 R12a;
C2-C6 alkenyl substituted with 0-3 R12a; or
C2-C6 alkynyl substituted with 0-3 R12a;
R12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, xe2x80x94C(xe2x95x90O)NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl-Sxe2x80x94,
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b; and wherein said 5 to 10 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
R14a is H, phenyl, benzyl, or C1-C4 alkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C4 alkyl)xe2x80x94C(xe2x95x90O)xe2x80x94, and (C1-C4 alkyl)xe2x80x94S(xe2x95x90O)2xe2x80x94;
R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, (C1-C4 alkyl)xe2x80x94C (xe2x95x90O)xe2x80x94, and (C1-C4 alkyl)xe2x80x94S(xe2x95x90O)2xe2x80x94;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)xe2x80x94C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)xe2x80x94S(xe2x95x90O)2xe2x80x94;
R19, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
provided when Q is xe2x80x94(CH2)nxe2x80x94N(R7b)xe2x80x94R4 and R7b is (C1-C4 alkyl)OC(xe2x95x90O)xe2x80x94, then n is 1 or 2; and
provided when Q is xe2x80x94(CH2)nxe2x80x94N(R7b)xe2x80x94R4 and n is 0, then R4 does not contain a xe2x80x94C(xe2x95x90O)xe2x80x94 adjacent to xe2x80x94N(R7b)xe2x80x94.
[5] In a further more preferred embodiment the present invention provides:
Q is xe2x80x94CH2R4, xe2x80x94CH2CH2R4, xe2x80x94CH2CH(OH)xe2x80x94R4, xe2x80x94CH2NH-R4, xe2x80x94CH2CH2NHR4, xe2x80x94CH2N(R7b)xe2x80x94R4, xe2x80x94CH2NHC(xe2x95x90O)xe2x80x94R4, or xe2x80x94NHxe2x80x94R4;
R4 is
C1-C6 alkyl substituted with 0-3 R4a,
C2-C6 alkenyl substituted with 0-3 R4a,
C2-C6 alkynyl substituted with 0-3 R4a,
C3-C6 carbocycle substituted with 0-3 R4b, phenyl substituted with 0-3 R4b, or
5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R4b;
R4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, CF3, methyl,
C3-C6 carbocycle substituted with 0--3 R4b,
phenyl substituted with 0-3 R4b, and
5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R5 and R5a are combined to form a 3-6 membered carbocyclic moiety;
wherein said 3-6 membered carbocyclic moiety is saturated or partially unsaturated;
wherein said 3-6 membered carbocyclic moiety may optionally contain a heteroatom selected from xe2x80x94Oxe2x80x94,
xe2x80x94NHxe2x80x94, and xe2x80x94N(R20)xe2x80x94; and wherein said 3-6 membered carbocyclic moiety is substituted with 0-2 R5b;
R5b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, methyl, ethyl, methoxy, ethoxy, allyl, xe2x80x94OCF3, and xe2x80x94SCF3;
R7b is H, methyl, ethyl, CH3C(xe2x95x90O)xe2x80x94, or CH3CH2OC(xe2x95x90O)xe2x80x94;
Ring B is selected from: 
R11, at each occurrence, is independently selected from H, xe2x95x90O, NR18R19, CF3;
C1-C4 alkyl optionally substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b ;
C3-C6 carbocycle substituted with 0-3 R11b; and
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R11a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl, xe2x95x90O, NR15NR16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H,
OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
W is a bond;
X is a bond;
Y is a bond;
Z is H;
C1-C4 alkyl substituted with 0-3 R12a;
C2-C4 alkenyl substituted with 0-3 R12a; or
C2-C4 alkynyl substituted with 0-3 R12a;
R12a, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R15, at each occurrence, is independently selected from H, C1-C4 alkyl, and benzyl;
R16, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(xe2x95x90O)xe2x80x9413 , ethyl-C(xe2x95x90O)xe2x80x94, methyl-S(xe2x95x90O)2xe2x80x94, and ethyl-S(xe2x95x90O)2xe2x80x94;
R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R19, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; and
provided when Q is xe2x80x94NHxe2x80x94R4, then R4 does not contain a xe2x80x94C(xe2x95x90O)xe2x80x94 adjacent to xe2x80x94N(R7b)xe2x80x94.
[6] In a further more preferred embodiment the present invention provides:
Q is xe2x80x94CH2R4, xe2x80x94CH2CH2R4, xe2x80x94CH2CH(OH)xe2x80x94R4, xe2x80x94CH2NHxe2x80x94R4, xe2x80x94CH2CH2NHR4, xe2x80x94CH2N(R7b)xe2x80x94R4, xe2x80x94CH2NHC(xe2x95x90O)xe2x80x94R4, or xe2x80x94NHxe2x80x94R4;
R4 is
C1-C6 alkyl substituted with 0-3 R4a,
C2-C6 alkenyl substituted with 0-3 R4a,
C2-C6 alkynyl substituted with 0-3 R4a,
C3-C6 carbocycle substituted with 0-3 R4b, or
phenyl substituted with 0-3 R4b;
R4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, CF3, methyl,
C3-C6 carbocycle substituted with 0-3 R4b,
phenyl substituted with 0-3 R4b, and
5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R4b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R4b, at each occurrence, is independently selected from H,
OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R5 and R5a are combined to form a 3-6 membered carbocyclic moiety selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and perhydro-2H-pyran; wherein said 3-6 membered carbocyclic moiety is substituted with 0-1 Rb 5b;
R5b is selected from H, OH, Cl, F, CN, CF3, methyl, ethyl, methoxy, ethoxy, allyl, and xe2x80x94OCF3;
R7b is H, methyl, ethyl, CH3OC(xe2x95x90O)xe2x80x94, or CH3CH2OC(xe2x95x90O)xe2x80x94;
Ring B is selected from: 
R11, at each occurrence, is independently selected from H, xe2x95x90O, NR18R19;
C1-C4 alkyl optionally substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R11a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl, xe2x95x90O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
W is a bond;
X is a bond;
Y is a bond;
Z is H;
C1-C4 alkyl substituted with 0-1 R12a;
C2-C4 alkenyl substituted with 0-1 R12a;
C2-C4 alkynyl substituted with 0-1 R12a;
R12a, at each occurrence, is independently selected from
H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R13, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN, NR15R16, and CF3;
R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R16, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, and phenethyl;
R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R19, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
provided when Q is xe2x80x94NHxe2x80x94R4, then R4 does not contain a
xe2x80x94C(xe2x95x90O)xe2x80x94 adjacent to xe2x80x94N(R7b)xe2x80x94.
[7] In a further more preferred embodiment the present invention provides:
R5 and R5a are combined to form cyclopentyl or cyclohexyl;
Q is
xe2x80x94CH2CH3,
xe2x80x94CH2CH2CH3,
xe2x80x94CH2CH2CH2CH3,
xe2x80x94CH2CH2CH2CH2CH3,
xe2x80x94CH2CH2CH2CH2CH2CH3,
xe2x80x94CH2CH(CH3)2,
xe2x80x94CH2CH2CH(CH3)2,
xe2x80x94CH2CH2CH2CH(CH3)2,
xe2x80x94CH2CH2CH2CH2CH(CH3)2,
xe2x80x94CH2NHCH2CH3,
xe2x80x94CH2NHCH2CH2CH3,
xe2x80x94CH2NHCH2CH2CH2CH3,
xe2x80x94CH2NHCH(CH3)2,
xe2x80x94CH2NHCH2CH(CH3)2,
xe2x80x94CH2NHCH2CH2CH(CH3)2,
xe2x80x94CH2CH(OH)CH2CH3,
xe2x80x94CH2CH(OH)CH2CH2CH3,
xe2x80x94CH2CH(OH)CH2CH2CH2CH3,
xe2x80x94CH2CH(OH)CH(CH3)2,
xe2x80x94CH2CH(OH)CH2CH(CH3)2,
xe2x80x94CH2CH(OH)CH2CH2CH(CH3)2,
xe2x80x94CH2CH(cyclopropyl),
xe2x80x94CH2CH2CH(cyclopropyl),
xe2x80x94CH2CH2CH2CH(cyclopropyl),
xe2x80x94CH2N(C(xe2x95x90O)OCH2CH3)CH2CH2CH (CH3)2,
xe2x80x94CH2NHC(xe2x95x90O)xe2x80x94CH2xe2x80x94(3,5-diF-phenyl),
xe2x80x94CH2NHC(xe2x95x90O)CH(OH)CH(CH3)2,
xe2x80x94CH2NHC(xe2x95x90O)CH(OH)CH2CH(CH3)2,
xe2x80x94CH2NHC (xe2x95x90O)CH(OH)CH2CH2CH3,
xe2x80x94CH2NHCH2CH(OH)CH2CH(CH3)2,
xe2x80x94CH2NHCH2CH(OH)CH2CH2CH3,
xe2x80x94CH2NHCH2CH(OH)CH2CH2CH2CH3,
xe2x80x94CH2NHCH2CH(OH)CH(CH3)2,
xe2x80x94CH2NHCH2CH2-(cyclopropyl),
xe2x80x94CH2NHCH2CH2-(cyclobutyl),
xe2x80x94CH2NHCH2CH2-(cyclopentyl),
xe2x80x94CH2NHCH2CH2-(cyclohexyl),
xe2x80x94CH2NHCH2-(cyclopropyl),
xe2x80x94CH2NHCH2-(cyclobutyl),
xe2x80x94CH2NHCH2-(cyclopentyl),
xe2x80x94CH2NHCH2-(cyclohexyl),
xe2x80x94CH2NH-(cyclopropyl),
xe2x80x94CH2NH-(cyclobutyl),
xe2x80x94CH2NH-(cyclopentyl),
xe2x80x94CH2NH-(cyclohexyl),
xe2x80x94CH2NHCH2CH2xe2x80x94(3,5-diF-phenyl),
xe2x80x94CH2NHCH2xe2x80x94(1,4-diF-phenyl),
xe2x80x94CH2CH2NHCH2CH(CH3)2,
xe2x80x94CH2CH2NHCH2CH2CH3,
xe2x80x94CH2CH2NHCH2CH2CH2CH3,
xe2x80x94CH2CH2NHCH2-(cyclopropyl),
xe2x80x94CH2CH2NHCH2-(cyclobutpyl),
xe2x80x94CH2CH2NHCH2-(cyclopentyl),
xe2x80x94CH2CH2NHCH2-(cyclohexyl),
xe2x80x94NHCH2CH(OH)CH(CH3)2,
xe2x80x94NHCH2CH(OH)-(cyclopropyl),
xe2x80x94NHCH2CH(OH)-(cyclobutyl),
xe2x80x94NHCH2CH(OH)-(cyclopentyl),
xe2x80x94NHCH2CH(OH)-(cyclohexyl), or
xe2x80x94CH2NHCH2CH(OH)-(phenyl);
W is a bond;
X is a bond;
Y is a bond;
Z is methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl, t-butyl, or allyl;
R11, at each occurrence, is independently selected from H, xe2x95x90O, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH2xe2x80x94, (4-F-phenyl)CH2CH2xe2x80x94, 3-F-phenyl, (3-F-phenyl)CH2xe2x80x94, (3-F-phenyl)CH2CH2xe2x80x94, 2-F-phenyl, (2-F-phenyl)CH2xe2x80x94, (2-F-phenyl)CH2CH2xe2x80x94, 4-Cl-phenyl, (4-Cl-phenyl)CH2xe2x80x94, (4-Cl-phenyl)CH2CH2xe2x80x94, 3-Cl-phenyl, (3-Cl-phenyl)CH2xe2x80x94, (3-Cl-phenyl)CH2CH2xe2x80x94, 4-CH3-phenyl, (4-CH3-phenyl)CH2xe2x80x94, (4-CH3-phenyl)CH2CH2xe2x80x94, 3-CH3-phenyl, (3-CH3-phenyl)CH2xe2x80x94, (3-CH3-phenyl)CH2CH2xe2x80x94, 4-CF3-phenyl, (4-CF3-phenyl)CH2xe2x80x94, (4-CF3-phenyl)CH2CH2xe2x80x94, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl; and
R13, at each occurrence, is independently selected from H, F, Cl, OH, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94OCH3, and xe2x80x94CF3.
[8] In a further more preferred embodiment the present invention provides for a compound of Formula (I):
wherein:
Q is
xe2x80x94(CH2)mxe2x80x94R4,
xe2x80x94(CH2)mxe2x80x94CH(OH)xe2x80x94R4,
xe2x80x94(CH2)mxe2x80x94NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)nxe2x80x94Sxe2x80x94R4,
xe2x80x94(CH2)nxe2x80x94Oxe2x80x94R4, or
xe2x80x94(CH2)nxe2x80x94N(R7b)xe2x80x94R4;
m is 1 or 2;
n is 0 or 1;
R4 is
C1-C8 alkyl substituted with 0-3 R4a,
C2-C8 alkenyl substituted with 0-3 R4a,
C2-C8 alkynyl substituted with 0-3 R4a,
C3-C10 carbocycle substituted with 0-3 R4b,
C6-C10 aryl substituted with 0-3 R4b, or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R4b;
R4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, CF3, methyl,
C3-C10 carbocycle substituted with 0-3 R4b,
C6-C10 aryl substituted with 0-3 R4b, and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R5 and R5aare combined to form a 3-8 membered carbocyclic moiety;
wherein said 3-8 membered carbocyclic moiety is saturated or partially unsaturated;
wherein said 3-8 membered carbocyclic moiety may optionally contain a heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94N(R20)xe2x80x94; and
wherein said 3-8 membered carbocyclic moiety is substituted with 0-3 R5b;
R5b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, NR15R16, OR14a, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R7b is H, methyl, ethyl, CH3OC(xe2x95x90O)xe2x80x94, or CH3CH2OC(xe2x95x90O)xe2x80x94;
Ring B is selected from: 
R11, at each occurrence, is independently selected from H, xe2x95x90O, NR18R19, CF3;
C1-C4 alkyl optionally substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
C3-C6 carbocycle substituted with 0-3 R11b; and
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R11a, at each occurrence, is independently selected from H,
C1-C4 alkyl, OR14, F, Cl, xe2x95x90O, NR15R16, CF3, and phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H,
OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
W is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94;
X is a bond;
phenyl substituted with 0-2 RXb;
C3-C6 cycloalkyl substituted with 0-2 RXb; or
5 to 6 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1xe2x80x94C2 haloalkoxy;
Y is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94N(R9)xe2x80x94, xe2x80x94C(xe2x95x90O)NR19bxe2x80x94, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94, xe2x80x94S (xe2x95x90O)NR19bxe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, or xe2x80x94OC(xe2x95x90O)xe2x80x94;
Z is
C1-C3 alkyl substituted with 1-2 R12a;
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-3 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12a, at each occurrence, is independently selected from
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is phenyl, benzyl, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
R14a is H, phenyl, benzyl, or C1-C4 alkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C4 alkyl)xe2x80x94C(xe2x95x90O)xe2x80x94, and (C1-C4 alkyl)xe2x80x94S(xe2x95x90O)2xe2x80x94;
R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, (C1-C4 alkyl)xe2x80x94C(xe2x95x90O)xe2x80x94, and (C1-C4 alkyl)xe2x80x94S(xe2x95x90O)2xe2x80x94;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)xe2x80x94C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)xe2x80x94S(xe2x95x90O)2xe2x80x94;
R19, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R9b, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
provided when Q is xe2x80x94(CH2)nxe2x80x94N(R7b)xe2x80x94R4 and R7b is (C1-C4 alkyl)OC(xe2x95x90O)xe2x80x94, then n is 1 or 2; and
provided when Q is xe2x80x94(CH2)nxe2x80x94N(R7b)xe2x80x94R4 and n is 0, then R4 does not contain a xe2x80x94C(xe2x95x90O)xe2x80x94 adjacent to xe2x80x94N(R7b)xe2x80x94.
[9] In a further more preferred embodiment the present invention provides:
Q is xe2x80x94CH2R4, xe2x80x94CH2CH2R4, xe2x80x94CH2CH(OH)xe2x80x94R4, xe2x80x94CH2NHxe2x80x94R4, xe2x80x94CH2CH2NHR4, xe2x80x94CH2N(R7b)xe2x80x94R4, xe2x80x94CH2NHC (xe2x95x90O)xe2x80x94R4, or xe2x80x94NHxe2x80x94R4;
R4 is
C1-C6 alkyl substituted with 0-3 R4a,
C2-C6 alkenyl substituted with 0-3 R4a,
C2-C6 alkynyl substituted with 0-3 R4a,
C3-C6 carbocycle substituted with 0-3 R4b,
phenyl substituted with 0-3 R4b, or
5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R4b;
R4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, CF3, methyl,
C3-C6 carbocycle substituted with 0-3 R4b,
phenyl substituted with 0-3 R4b, and
5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R5 and R5a are combined to form a 3-6 membered carbocyclic moiety;
wherein said 3-6 membered carbocyclic moiety is saturated or partially unsaturated;
wherein said 3-6 membered carbocyclic moiety may optionally contain a heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94N(R20)xe2x80x94; and
wherein said 3-6 membered carbocyclic moiety is substituted with 0-2 R5b;
R5b, at each occurrence, is independently selected from H,
OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, methyl, ethyl, methoxy, ethoxy, allyl, xe2x80x94OCF3, and xe2x80x94SCF3;
R7b is H, methyl, ethyl, CH3OC(xe2x95x90O)xe2x80x94, or CH3CH2OC(xe2x95x90O)xe2x80x94;
Ring B is selected from: 
R11, at each occurrence, is independently selected from
H, xe2x95x90O, NR18R19, CF3;
C1-C4 alkyl optionally substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
C3-C6 carbocycle substituted with 0-3 R11b; and
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R11a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl, xe2x95x90O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
W is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94;
X is a bond;
phenyl substituted with 0-1 RXb;
C3-C6 cycloalkyl substituted with 0-1 RXb; or
5 to 6 membered heterocycle substituted with 0-1 RXb;
RXb is selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, and xe2x80x94OCF3;
Y is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(CH3)xe2x80x94, or xe2x80x94N(CH2CH3)xe2x80x94;
Z is C1-C2 alkyl substituted with 1-2 R12a;
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-3 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12a, at each occurrence, is independently selected from C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, Sxe2x80x94(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C4 alkyl, or C2-C4 alkoxyalkyl;
R15, at each occurrence, is independently selected from H,
C1-C4 alkyl, and benzyl;
R16, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(xe2x95x90O)xe2x80x94, ethyl-C(xe2x95x90O)xe2x80x94, methyl-S(xe2x95x90O)2xe2x80x94, and ethyl-S(xe2x95x90O)2xe2x80x94;
R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R19, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; and
provided when Q is xe2x80x94(CH2)nxe2x80x94N(R7b)xe2x80x94R4 and R7b is (C1-C4 alkyl)OC(xe2x95x90O)xe2x80x94, then n is 1 or 2; and
provided when Q is xe2x80x94(CH2)nxe2x80x94N(R7b)xe2x80x94R4 and n is O, then R4 does not contain a xe2x80x94C(xe2x95x90O)xe2x80x94 adjacent to xe2x80x94N(R7b)xe2x80x94.
[10] In a further more preferred embodiment the present invention provides:
Q is xe2x80x94CH2R4, xe2x80x94CH2CH2R4, xe2x80x94CH2CH(OH)xe2x80x94R4, xe2x80x94CH2NHxe2x80x94R4, xe2x80x94CH2CH2NHR4, xe2x80x94CH2N(R7b)xe2x80x94R4, xe2x80x94CH2NHC (xe2x95x90O)xe2x80x94R4, or xe2x80x94NHxe2x80x94R4;
R4 is
C1-C6 alkyl substituted with 0-3 R4a,
C2-C6 alkenyl substituted with 0-3 R4a,
C2-C6 alkynyl substituted with 0-3 R4a,
C3-C6 carbocycle substituted with 0-3 R4b, or
phenyl substituted with 0-3 R4b;
R4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, CF3, methyl,
C3-C6 carbocycle substituted with 0-3 R4b,
phenyl substituted with 0-3 R4b, and
5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R4b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R5 and R5a are combined to form a 3-6 membered carbocyclic moiety selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and perhydro-2H-pyran; wherein said 3-6 membered carbocyclic moiety is substituted with 0-1 R5b;
R5b is selected from H, OH, Cl, F, CN, CF3, methyl, ethyl, methoxy, ethoxy, allyl, and xe2x80x94OCF3;
R7b is H, methyl, ethyl, CH3OC(xe2x95x90O)xe2x80x94, or CH3CH2OC(xe2x95x90O)xe2x80x94;
Ring B is selected from: 
R11, at each occurrence, is independently selected from H, xe2x95x90O, NR18R19;
C1-C4 alkyl optionally substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R11a, at each occurrence, is independently selected from H,
methyl, ethyl, propyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl, xe2x95x90O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H,
OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
W is a bond or xe2x80x94CH2xe2x80x94;
X is a bond;
phenyl substituted with 0-1 RXb;
C3-C6 cycloalkyl substituted with 0-1 RXb; or
5 to 6 membered heterocycle substituted with 0-1 RXb;
RXb is selected from H, OH, Cl, F, NR15R16, CF3, acetyl, methyl, ethyl, methoxy, ethoxy, and xe2x80x94OCF3;
Y is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(CH3)xe2x80x94, or xe2x80x94N(CH2CH3)xe2x80x94;
Z is
C1-C2 alkyl substituted with 1-2 R12a;
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-3 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12a, at each occurrence, is independently selected from C6-C10 aryl substituted with 0-4 R12b);
C3-C10 carbocycle substituted with 0-4 R12b; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b; and wherein said 5 to 10 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and xe2x80x94OCF3;
R13, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN, NR15R16, and CF3;
R14 is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;
R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R16, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, and phenethyl;
R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R19, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; and
provided when Q is xe2x80x94NHxe2x80x94R4, then R4 does not contain a xe2x80x94C(xe2x95x90O)xe2x80x94 adjacent to xe2x80x94N(R7b)xe2x80x94.
[11] In a further more preferred embodiment the present invention provides:
R5 and R5a are combined to form cyclopentyl or cyclohexyl;
Q is
xe2x80x94CH2CH3,
xe2x80x94CH2CH2CH3,
xe2x80x94CH2CH2CH2CH3,
xe2x80x94CH2CH2CH2CH2CH3,
xe2x80x94CH2CH2CH2CH2CH2CH3,
xe2x80x94CH2CH(CH3)2,
xe2x80x94CH2CH2CH(CH3)2,
xe2x80x94CH2CH2CH2CH(CH3)2,
xe2x80x94CH2CH2CH2CH2CH(CH3)2,
xe2x80x94CH2NHCH2CH3,
xe2x80x94CH2NHCH2CH2CH3,
xe2x80x94CH2NHCH2CH2CH2CH3,
xe2x80x94CH2NHCH(CH3)2,
xe2x80x94CH2NHCH2CH(CH3)2,
xe2x80x94CH2NHCH2CH2CH(CH3)2,
xe2x80x94CH2CH(OH)CH2CH3,
xe2x80x94CH2CH(OH)CH2CH2CH3,
xe2x80x94CH2CH(OH)CH2CH2CH2CH3,
xe2x80x94CH2CH(OH)CH(CH3)2,
xe2x80x94CH2CH(OH)CH2CH(CH3)2,
xe2x80x94CH2CH(OH)CH2CH2CH(CH3)2,
xe2x80x94CH2CH(cyclopropyl),
xe2x80x94CH2CH2CH(cyclopropyl),
xe2x80x94CH2CH2CH2CH (cyclopropyl),
xe2x80x94CH2N(C(xe2x95x90O)OCH2CH3)CH2CH2CH(CH3)2,
xe2x80x94CH2NHC(xe2x95x90O)xe2x80x94CH2-(3,5-diF-phenyl),
xe2x80x94CH2NHC(xe2x95x90O)CH(OH)CH(CH3)2,
xe2x80x94CH2NHC(xe2x95x90O)CH(OH)CH2CH(CH3)2,
xe2x80x94CH2NHC(xe2x95x90O)CH(OH)CH2CH2CH3,
xe2x80x94CH2NHCH2CH(OH)CH2CH(CH3)2,
xe2x80x94CH2NHCH2CH(OH)CH2CH2CH3,
xe2x80x94CH2NHCH2CH(OH)CH2CH2CH2CH3,
xe2x80x94CH2NHCH2CH(OH)CH(CH3)2,
xe2x80x94CH2NHCH2CH2-(cyclopropyl),
xe2x80x94CH2NHCH2CH2-(cyclobutyl),
xe2x80x94CH2NHCH2CH2-(cyclopentyl),
xe2x80x94CH2NHCH2CH2-(cyclohexyl),
xe2x80x94CH2NHCH2-(cyclopropyl),
xe2x80x94CH2NHCH2-(cyclobutyl),
xe2x80x94CH2NHCH2-(cyclopentyl),
xe2x80x94CH2NHCH2-(cyclohexyl),
xe2x80x94CH2NH-(cyclopropyl),
xe2x80x94CH2NH-(cyclobutyl),
xe2x80x94CH2NH-(cyclopentyl),
xe2x80x94CH2NH-(cyclohexyl),
xe2x80x94CH2NHCH2CH2xe2x80x94(3,5-diF-phenyl),
xe2x80x94CH2NHCH2xe2x80x94(1,4-diF-phenyl),
xe2x80x94CH2CH2NHCH2CH(CH3)2,
xe2x80x94CH2CH2NHCH2CH2CH3,
xe2x80x94CH2CH2NHCH2CH2CH2CH3,
xe2x80x94CH2CH2NHCH2-(cyclopropyl),
xe2x80x94CH2CH2NHCH2-(cyclobutpyl),
xe2x80x94CH2CH2NHCH2-(cyclopentyl),
xe2x80x94CH2CH2NHCH2-(cyclohexyl),
xe2x80x94NHCH2CH(OH)CH(CH3)2,
xe2x80x94NHCH2CH(OH)-(cyclopropyl),
xe2x80x94NHCH2CH(OH)-(cyclobutyl),
xe2x80x94NHCH2CH(OH)-(cyclopentyl),
xe2x80x94NHCH2CH(OH)-(cyclohexyl), or
xe2x80x94CH2NHCH2CH(OH)-(phenyl);
W is a bond or xe2x80x94CH2xe2x80x94;
X is a bond; 
Y is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94N(CH3)xe2x80x94,
Z is phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF3O-phenyl, 3-CF3O-phenyl, 4-CF3O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl, phenyl-CH2xe2x80x94, (2-F-phenyl)CH2xe2x80x94, (3-F-phenyl)CH2xe2x80x94, (4-F-phenyl)CH2xe2x80x94, (2-Cl-phenyl)CH2xe2x80x94, (3-Cl-phenyl)CH2, (4-Cl-phenyl)CH2xe2x80x94, (2,3-diF-phenyl)CH2xe2x80x94, (2,4-diF-phenyl)CH2xe2x80x94, (2,5-diF-phenyl)CH2xe2x80x94, (2,6-diF-phenyl)CH2xe2x80x94, (3,4-diF-phenyl)CH2xe2x80x94, (3,5-diF-phenyl)CH2xe2x80x94, (2,3-diCl-phenyl)CH2xe2x80x94, (2,4-diCl-phenyl)CH2xe2x80x94, (2,5-diCl-phenyl)CH2xe2x80x94, (2,6-diCl-phenyl)CH2xe2x80x94, (3,4-diCl-phenyl)CH2xe2x80x94, (3,5-diCl-phenyl)CH2xe2x80x94, (3-F-4-Cl-phenyl)CH2xe2x80x94, (3-F-5-Cl-phenyl)CH2xe2x80x94, (3-Cl-4-F-phenyl)CH2xe2x80x94, (2-MeO-phenyl)CH2xe2x80x94, (3-MeO-phenyl)CH2xe2x80x94, (4-MeO-phenyl)CH2xe2x80x94, (2-Me-phenyl)CH2xe2x80x94, (3-Me-phenyl)CH2xe2x80x94, (4-Me-phenyl)CH2xe2x80x94, (2-MeS-phenyl)CH2xe2x80x94, (3-MeS-phenyl)CH2xe2x80x94, 4-MeS-phenyl)CH2xe2x80x94, (2-CF3O-phenyl)CH2xe2x80x94, (3-CF3O-phenyl)CH2xe2x80x94, (4-CF3O-phenyl)CH2xe2x80x94, (furanyl)CH2xe2x80x94,(thienyl)CH2xe2x80x94, (pyridyl)CH2xe2x80x94, (2-Me-pyridyl)CH2xe2x80x94, (3-Me-pyridyl)CH2xe2x80x94, (4-Me-pyridyl)CH2xe2x80x94, (1-imidazolyl)CH2xe2x80x94, (oxazolyl)CH2xe2x80x94, (isoxazolyl)CH2xe2x80x94, (1-benzimidazolyl)CH2xe2x80x94, (cyclopropyl)CH2xe2x80x94, (cyclobutyl)CH2xe2x80x94, (cyclopentyl)CH2xe2x80x94, (cyclohexyl)CH2xe2x80x94, (morpholino)CH2xe2x80x94, (N-pipridinyl)CH2xe2x80x94, phenyl-CH2CH2xe2x80x94, (phenyl)2CHCH2xe2x80x94, (2-F-phenyl)CH2CH2xe2x80x94, (3-F-phenyl)CH2CH2xe2x80x94, (4-F-phenyl)CH2CH2xe2x80x94, (2-Cl-phenyl)CH2CH2xe2x80x94, (3-Cl-phenyl)CH2CH2xe2x80x94, (4-Cl-phenyl)CH2CH2xe2x80x94, (2,3-diF-phenyl)CH2CH2xe2x80x94, (2,4-diF-phenyl)CH2CH2xe2x80x94, (2,5-diF-phenyl)CH2CH2xe2x80x94, (2,6-diF-phenyl)CH2CH2xe2x80x94, (3,4-diF-phenyl)CH2CH2xe2x80x94, (3,5-diF-phenyl)CH2CH2xe2x80x94, (2,3-diCl-phenyl)CH2CH2xe2x80x94, (2,4-diCl-phenyl)CH2CH2xe2x80x94, (2,5-diCl-phenyl)CH2CH2xe2x80x94, (2,6-diCl-phenyl)CH2CH2xe2x80x94, (3,4-diCl-phenyl)CH2CH2xe2x80x94, (3,5-diCl-phenyl)CH2CH2xe2x80x94, (3-F-4-Cl-phenyl)CH2CH2xe2x80x94, (3-F-5-Cl-phenyl)CH2CH2xe2x80x94, (3-Cl-4-F-phenyl)CH2CH2xe2x80x94, (2-MeO-phenyl)CH2CH2xe2x80x94, (3-MeO-phenyl)CH2CH2xe2x80x94, (4-MeO-phenyl)CH2CH2xe2x80x94, (2-Me-phenyl)CH2CH2xe2x80x94, (3-Me-phenyl)CH2CH2xe2x80x94, (4-Me-phenyl)CH2CH2xe2x80x94, (2-MeS-phenyl)CH2CH2xe2x80x94, (3-MeS-phenyl)CH2CH2xe2x80x94, (4-MeS-phenyl)CH2CH2xe2x80x94, (2-CF3O-phenyl)CH2CH2xe2x80x94, (3-CF3O-phenyl)CH2CH2xe2x80x94, (4-CF3O-phenyl)CH2CH2xe2x80x94, furanyl)CH2CH2xe2x80x94, (thienyl)CH2CH2xe2x80x94, (pyridyl)CH2CH2xe2x80x94, (2-Me-pyridyl)CH2CH2xe2x80x94, (3-Me-pyridyl)CH2CH2xe2x80x94, (4-Me-pyridyl)CH2CH2xe2x80x94, (imidazolyl)CH2CH2xe2x80x94, (oxazolyl)CH2CH2xe2x80x94, (isoxazolyl)CH2CH2xe2x80x94, (benzimidazolyl)CH2CH2xe2x80x94,(cyclopropyl)CH2CH2xe2x80x94, (cyclobutyl)CH2CH2xe2x80x94,(cyclopentyl)CH2CH2xe2x80x94, (cyclohexyl)CH2CH2xe2x80x94,(morpholino)CH2CH2xe2x80x94, or (N-pipridinyl)CH2CH2xe2x80x94;
R11, at each occurrence, is independently selected from H, xe2x95x90O, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH2xe2x80x94, (4-F-phenyl)CH2CH2xe2x80x94, 3-F-phenyl, (3-F-phenyl)CH2xe2x80x94, (3-F-phenyl)CH2CH2xe2x80x94, 2-F-phenyl, (2-F-phenyl)CH2xe2x80x94, (2-F-phenyl)CH2CH2xe2x80x94, 4-Cl-phenyl, (4-Cl-phenyl)CH2xe2x80x94, (4-Cl-phenyl)CH2CH2xe2x80x94, 3-Cl-phenyl, (3-Cl-phenyl)CH2xe2x80x94, (3-Cl-phenyl)CH2CH2xe2x80x94, 4xe2x80x94CH3-phenyl, (4xe2x80x94CH3-phenyl)CH2xe2x80x94, (4xe2x80x94CH3-phenyl)CH2CH2xe2x80x94, 3xe2x80x94CH3-phenyl, (3xe2x80x94CH3-phenyl)CH2xe2x80x94, (3xe2x80x94CH3-phenyl)CH2CH2xe2x80x94, 4-CF3-phenyl, (4-CF3-phenyl)CH2xe2x80x94, (4-CF3-phenyl)CH2CH2xe2x80x94, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl; and
R13, at each occurrence, is independently selected from H, F, Cl, OH, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94OCH3, and xe2x80x94CF3.
[12] In a further more preferred embodiment the present invention provides for a compound of Formula (Ic): 
or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof.
[13] In a further more preferred embodiment the present invention provides for a compound of Formula (Id): 
or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof.
[14] In a further more preferred embodiment the present invention provides for a compound of Formula (Ie): 
or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof.
[15] In a further more preferred embodiment the present invention provides for a compound of Formula (Ie): 
or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof.
[16] In a further even more preferred embodiment the present invention provides for a compound selected from:
1-{[(3-methylbutyl)amino]methyl}-N-[6,7-dihydro-5-methyl-6-oxo-5H-dibenzo[b,d]azepin-7-yl]-cyclopentanecarbocyclic amide;
1{[Nxe2x80x2-(ethoxycarbonyl)-Nxe2x80x2-(3-methylbutyl)amino]methyl}-N-[6,7-dihydro-5-methyl-6-oxo-5H-dibenzo[b,d]azepin-7-yl]-cyclopentanecarbocyclic amide;
4-{[(3-methylbutyl)amino]methyl}-4-{N-[6,7-dihydro-5-methyl-6-oxo-5H-dibenzo[b,d]azepin-7-yl]carbamoyl}-perhydro-2H-pyran;
1-(2-hydroxy-pentyl)-N-[6,7-dihydro-5-methyl-6-oxo-5H-dibenzo[b,d]azepin-7-yl]-cyclopentanecarbocyclic amide;
4-{[[(3,5-difluorophenyl)methyl]amido]methyl}-4-{N-[6,7-dihydro-5-methyl-6-oxo-5H-dibenzo[b,d]azepin-7-yl]carbamoyl}-perhydro-2H-pyran;
2-(S)-hydroxy-3-methyl-N-({[N-(5-methyl-6-oxo (7H-dibenzo [d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}methyl)butanamide;
2-(S)-hydroxy-4-methyl-N-({[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}methyl)pentanamide;
2-(3,5-difluorophenyl)-N-({[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}methyl)acetamide;
N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))({2-[(2-methylpropyl)amino]ethyl}cyclopentyl)carboxamide;
({2-[(cyclopropylmethyl)amino]ethyl}cyclopentyl)-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;
[({[2-(3,5-difluorophenyl)ethyl]amino}methyl)cyclopentyl]-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;
[({[(1,4-difluorophenyl)methyl]amino}methyl)cyclopentyl]-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;
({[(2-cyclopentylethyl)amino]methyl}cyclopentyl)-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;
{[((2S)-2-hydroxy-4-methylpentyl)amino]cyclopentyl}-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;
{[((2S)-2-hydroxy-3-methylbutyl)amino]cyclopentyl}-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;
{[((2S)-2-cyclohexyl-2-hydroxyethyl)amino]cyclopentyl}-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;
1-{[(3-methylbutylamino]methyl}-N-{(S)-1,3-dihydro-1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl]-2H-1,4-benzodiazepin-3-yl}-cyclopentanecarbocylic amide;
1-(5-methyl)hexyl-N-{(S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl}-cyclopentanecarbocylic amide;
1-pentyl-N-{(S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl}-cyclopentanecarbocylic amide;
1-(2-hydroxypentyl)-N-{(S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl}-cyclopentanecarbocylic amide;
2-(S)-hydroxy-3-methyl-N-{[(N-{1 -methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]methyl}butanamide;
(2S)-N-({[N-(7-fluoro-1-methyl-2-oxo-5-phenyl(3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}methyl)-2-hydroxy-3-methylbutanamide;
(2S)-N-({[N-(5-cyclopentyl-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}methyl)-2-hydroxy-3-methylbutanamide;
{[(cyclohexylamino)methyl]cyclopentyl}-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;
({[(2-hydroxyhexyl)amino]methyl}cyclopentyl)-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide;
({[((2R)-2-hydroxy-2-phenylethyl)amino]methyl}cyclopentyl)-N-{l-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide; and
({[((2S)-2-hydroxy-2-phenylethyl)amino]methyl}cyclopentyl)-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide.
It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional even more preferred embodiments of the present invention.
In a second embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
In a third embodiment, the present invention provides a method for the treatment of neurological disorders associated with xcex2-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I).
In a preferred embodiment the neurological disorder associated with xcex2-amyloid production is Alzheimer""s Disease.
In a fourth embodiment, the present invention provides a method for inhibiting xcex3-secretase activity for the treatment of a physiological disorder associated with inhibiting xcex3-secretase activity comprising administering to a host in need of such inhibition a therapeutically effective amount of a compound of Formula (I) that inhibits xcex3-secretase activity.
Thus, the present invention provides a method for inhibiting xcex3-secretase activity comprising administering to a host in need of such inhibition a therapeutically effective amount of a compound of Formula (I) that inhibits xcex3-secretase activity.
In a preferred embodiment the physiological disorder associated with inhibiting xcex3-secretase activity is Alzheimer""s Disease.
In a fifth embodiment, the present invention provides a compound of Formula (I) for use in therapy.
In a preferred embodiment the present invention provides a compound of Formula (I) for use in therapy of Alzheimer""s Disease.
In a sixth embodiment, the present invention provides for the use of a compound of Formula (I) for the manufacture of a medicament for the treatment of Alzheimer""s Disease.
As used herein, the term xe2x80x9cAxcex2xe2x80x9d denotes the protein designated Axcex2, xcex2-amyloid peptide, and sometimes xcex2/A4, in the art. Axcex2 is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids found in amyloid plaques, the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No. 4,666,829. The 43 amino acid sequence is:
The term xe2x80x9cAPPxe2x80x9d, as used herein, refers to the protein known in the art as xcex2 amyloid precursor protein. This protein is the precursor for Axcex2 and through the activity of xe2x80x9csecretasexe2x80x9d enzymes, as used herein, it is processed into Axcex2. Differing secretase enzymes, known in the art, have been designated xcex2 secretase, generating the N-terminus of Axcex2, xcex1 secretase cleaving around the 16/17 peptide bond in Axcex2, and xe2x80x9cxcex3 secretasesxe2x80x9d, as used herein, generating C-terminal Axcex2 fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e. xe2x95x90O), then 2 hydrogens on the atom are replaced.
When any variable (e.g. R5b) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R5b, then said group may optionally be substituted with up to two R5b groups and R5b at each occurrence is selected independently from the definition of R5b. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, xe2x80x9cC1-C6 alkylxe2x80x9d denotes alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. Preferred xe2x80x9calkylxe2x80x9d group, unless otherwise specified, is xe2x80x9cC1-C4 alkylxe2x80x9d. Additionally, unless otherwise specified, xe2x80x9cpropylxe2x80x9d denotes n-propyl or i-propyl; xe2x80x9cbutylxe2x80x9d denotes n-butyl, i-butyl, sec-butyl, or t-butyl.
As used herein, xe2x80x9calkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbonxe2x80x94carbon bonds which may occur in any stable point along the chain. Examples of xe2x80x9cC2-C6 alkenylxe2x80x9d include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl, hexenyl, and the like.
As used herein, xe2x80x9calkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbonxe2x80x94carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d or xe2x80x9calkyloxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy. Similarly, xe2x80x9calkylthioxe2x80x9d or xe2x80x9cthioalkoxyxe2x80x9d is represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo. Unless otherwise specified, preferred halo is fluoro and chloro. xe2x80x9cCounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, heptafluoropropyl, and heptachloropropyl. xe2x80x9cHaloalkoxyxe2x80x9d is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge; for example trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy, and the like. xe2x80x9cHalothioalkoxyxe2x80x9d is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, having the specified number of carbon atoms. For example, xe2x80x9cC3-C6 cycloalkylxe2x80x9d denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
As used herein, xe2x80x9ccarbocyclexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). Preferred xe2x80x9ccarbocyclexe2x80x9d are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
As used herein, xe2x80x9ccarbocyclic moietyxe2x80x9d is intended to mean any stable 3- to 8-membered monocyclic ring of carbon atoms, any of which may be saturated or partially unsaturated. Additionally, the 3 to 8 membered monocyclic ring of carbon atoms may be contain a heteroatom selected from oxygen, sulphur, or nitrogen, wherein a carbon atom of the ring has been substituted for the heteroatom. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopent-3-enyl, cyclohex-3-enyl, tetrahydrofurnayl, pyranyl, pyrrolidinyl, and piperidinyl. Preferred examples of a xe2x80x9ccarbocyclic moietyxe2x80x9d are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic ringxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl. Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl; more preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, and tetrazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, the term xe2x80x9carylxe2x80x9d, xe2x80x9cC6-C10 arylxe2x80x9d or aromatic residue, is intended to mean an aromatic moiety containing the specified number of carbon atoms; for example phenyl, pyridinyl or naphthyl. Preferred xe2x80x9carylxe2x80x9d is phenyl. Unless otherwise specified, xe2x80x9carylxe2x80x9d may be unsubstituted or substituted with 0 to 3 groups selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, amino, hydroxy, Cl, F, Br, I, CF3, SCH3, S(O)CH3, SO2CH3, xe2x80x94N(CH3)2, N(CH3)H, CN, NO2, OCF3, C(xe2x95x90O)CH3, CO2H, CO2CH3, or C1-C4 haloalkyl.
As used herein, the term xe2x80x9cheteroaryl fused radicalxe2x80x9d is intended to denote a 5 or 6 membered aromatic ring comprising carbon atoms and one or two heteroatoms selected from nitrogen, sulphur and oxygen. The 5 or 6 membered ring is fused to two adjacent atoms of a second ring, i.e. a bicyclic ring system, wherein the second ring is a xe2x80x9ccarbocyclic moietyxe2x80x9d as defined above. Examples of a xe2x80x9cheteroaryl fused radicalxe2x80x9d are furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, thiophenyl, thiazolyl, isothiozalyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
The phrase xe2x80x9cadditional lactam carbonsxe2x80x9d, as used herein, is intended to denote the number of optional carbon atoms in the lactam ring B of Formula (I). Formula (Ixe2x80x3): 
represents the lactam ring B of Formula (I). Additional lactam carbons are carbons in lactam ring B other than the carbons numbered 2 and 3 in the backbone of the formula. The additional lactam carbons may be optionally replaced by a heteroatom selected from oxygen, nitrogen and sulfur. Lactam ring B contains 1, 2, 3, 4, 5, 6 or 7 optional carbons, wherein one optional carbon may optionally be replaced by a heteroatom, such that the total number of members of lactam ring B, including atoms numbered 1, 2 and 3 in the backbone, does not exceed 10. It is preferred that the total number of atoms of lactam ring B is 6, 7 or 8; it is more preferred that the total number of atoms of lactam ring B is seven. It is further understood that lactam ring B may optionally be unsaturated or partially unsaturated (i.e. two adjacent atoms in the ring form a double bond) wherein the backbone of lactam ring B may contain one, two or three double bonds. Examples of lactam ring B include: 
but are not intended to limit the invention. Preferred examples of lactam ring B are B1, B2, B5, B6, B8, B9, B13, and B16; more preferred examples of lactam ring B are B1, B6, B8, B9, and B13. Preferred examples of substituent R10 or R11 on lactam B are hydrogen, methyl, ethyl, phenyl, benzyl, phenethyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-CF3-phenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-methylphenyl)methyl, (4-CF3-phenyl)methyl, (4-fluorophenyl)ethyl, (4-chlorophenyl)ethyl, (4-methylphenyl)ethyl, (4-CF3-phenyl)ethyl, and 2-, 3-, and 4-pyridinyl. More preferred examples of substituent R10 or R11 on lactam B are methyl, ethyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-CF3-phenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-CF3-phenyl)methyl, and 2-, 3-, and 4-pyridinyl. Preferred examples of R13 on lactam B are F, Cl, OH, methyl, ethyl, methoxy, and trifluoromethyl.
It is understood that the functional group of the formula xe2x80x94NHxe2x80x94C(OH)2xe2x80x94 is equivalent to xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94.
The compounds herein described may have asymmetric centers. One enantiomer of a compound of Formula (I) may display superior biological activity over the opposite enantiomer. For example carbon 3 of lactam ring B Formula (Ixe2x80x3) may exist in either an S or R configuration. Thus, an R or S configuration at carbon 3 in Formula (Ixe2x80x3) is considered part of the invention. An example of such configuration includes, the S isomer: 
but is not intended to be limited to this example of ring B. When required, separation of the racemic material can be achieved by methods known in the art.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of Formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula (I), and the like.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
In a preferred method of synthesis, the compounds of Formula (I) of the present invention can be prepared from carboxylic acid 1 and amine 2 using amide bond syntheses known in the art, including methods commonly used in peptide syntheses, such as HATU, TBTU, BOP, EDC, CDI, and DCC-mediated couplings, as illustrated in Scheme 1. Depending on the structure of the final product, it is appreciated by those skilled in the art that protecting groups or precursor functionality convertible to the desired groups may be desirable. Protecting groups and their use in synthesis are described in Green and Wuts, Protective Groups in Organic Synthesis, (Wiley 1991). 
Additionally, the syntheses of a representative aminomethyl carboxamide 4a, lactate 7b, and a representative homoaldol 4c of Formula (I) are illustrated in Scheme 2 and Scheme 3, respectively. As will be readily apparent to those of ordinary skill in the art, the synthetic procedures illustrated in Scheme 2 and 3, and the reaction conditions described below can be modified by selecting the appropriate starting materials and reagents to allow the preparation of other compounds of the present invention. 
Methods for the synthesis of lactams useful as intermediates in the synthesis of compounds of the present invention, including amino bisbenzodiazepine 5 and amino benzodiazepine 8, are known in the art and are disclosed in a number of references including PCT publication number WO 98/28268, WO 99/66934, and WO00/07995, which are hereby incorporated by reference. Additional references include Bock, et. al., J. Org. Chem., 1987, 52, 3232-3239; Sherrill et. al., J. Org. Chem., 1995, 60, 730-734; Walsh, D. A., Synthesis, September 1980, p. 677; and Brown, at. al., Tetrahedron Letters, 1971, 8, 667-670.
Aminomethyl cyclic carboxylic acid intermediates, such as 4a, are useful for the synthesis of the current invention, and may be synthesized by a number of ways well known in the art. One of the preferred syntheses of the compound of this invention is shown in Scheme 4. Potassium carbonate-promoted double alkylation reaction of methyl ester 10 can be employed to give the cyclic ester 11. The cyanocarboxylic ester 11 is readily reduced to the corresponding amine under the reaction conditions described by Brown, R. R. et al., Synthesis, 1982, 1036. The completion of intermediate 4a can be achieved by performing the reductive amination reaction on 12 (J. Org. Chem., 1996, 61, 3849-3862), followed by the hydrolysis of ester 13. It should be apparent to those of ordinary skill in the art that many derivatives of 4a can be prepared in a similar manner from the versatile intermediate 12, upon the selection of an appropriate starting material and following procedures known in the literature. 
One of the representative syntheses of homoaldol analogs, such as 15, is illustrated in Scheme 5. The useful intermediate lactones, such as 14, are known in the art and one of their syntheses are described in J. Org. Chem., 1996, 61, 3849-3862.
One of the preferred syntheses of cyclic lactates, such as 7b, which are useful in the preparation of compounds of Formula (I), is outlined in Scheme 6. As illustrated for the synthesis of carboxylic acid 7b, intermediate 17 can be prepared by from ester 16, under the reaction conditions which are known in the art and disclosed in a number of references including J. Org. Chem., 1986, 51, 2402, and Chem. Rev., 1992, 92, 919. Finally, adduct 7b can be prepared by the alkylation of 17 and hydrolysis of the resulting ester.
Depending on the structure of the final product, it is appreciated by those skilled in the art, the synthetic procedure illustrated in Scheme 4, 5, and 6 and the reaction conditions described will allow the preparation of many other analogs of 4 and 7 by selecting the appropriate starting materials and reagents. Many of the starting materials employed in this invention are either commercially available or can be prepared from commercially available materials using conventional procedures and reagents. 
In order to assist in a further understanding of the current invention, one of the representative syntheses of the final inhibitors, such as compound 23, is illustrated in Scheme 7. Target 23 was prepared in 5 steps beginning with starting materials 10 and 18. The initial intermediate 12 was easily prepared under the reaction conditions that are know in the art (Justus Liebigs Ann. Chem. GE., 639, 1961, 166-180 and Helv. Chim. Acta. 1998, 2218-2243). EDC-promoted coupling reaction of the acid 19 and 12 provided the intermediate 20 that was subsequently hydrolyzed by LiOH and coupled with the amine 22 to give the final product 23. 
In order to assist in a further understanding of the current invention, one of the representative syntheses of the amino alcohol APP inhibitors, such as compound 30, is illustrated in Scheme 8. Molecule 30 was prepared in 5 steps. The starting aldehyde 25 was synthesized according to the published procedure of Chem. Lett 1992, 1169-1172. All other reaction conditions are known in the art. The employed reductive amination reaction was describe in J. Org. Chem., 1996, 61, 3849.
Abbreviations used in the description of the chemistry and in the examples that follow are: